The long term objective of this program project continues to be to elucidate the role of biobehavioral factors in the etiology, pathogenesis and course of coronary heart disease (CHD). Our integrative theme has expanded from its primary focus on hostility to include a set of psychosocial, behavioral and biological characteristics that increase (SES). To pursue this theme, investigators with a variety of disciplinary backgrounds - psychiatry, medicine, psychology, pharmacology, pathology, biostatistics, epidemiology, molecular biology and neurobiology - will work to achieve three broad, programmatic objectives: 1) Evaluate the association between interrelated sets of psychosocial risk factors and behavioral and biological (including the cellular/molecular level) mediators of pathogenesis; 2) Identify environmental antecedents of the psychosocial/behavioral profile that increase pathogenesis; and 3) Evaluate in both humans and an animal model the possible role of reduced brain serotonergic function as a mediator of the clustering in certain individuals and low SES groups of psychosocial and biobehavioral mediators of pathogenesis. Project 1 will evaluate the association between psychosocial risk factors and biological mechanisms at both the "macro" and cellular levels that could be responsible for pathogenesis, with a special focus on low SES as an amplifer of psychosocial effects on biological mediators. Project 2 will evaluate the relation of brain serotonergic function to the set of psychosocial and biobehavioral risk mediators in Project 1's community sample of 400 persons stratified for SES, race and gender. Project 3 will use three ongoing large scale studies of Caucasian, American Indian, and African American boys and girls to evaluate the impact of harsh environments on the emergence of the adverse psychosocial/biobehavioral profile. Project 4 will use a rat model to evaluate the impact of early maternal deprivation on the development of biobehavioral characteristics analogous to those seen in humans with the adverse profile, and it will evaluate the role of brain serotonin in mediating this environmental impact. Resuults should enhance our understanding of the environmental and neurobiological bases of the clustering of psychsocial/biobehavioral risk factors in certain individuals and low SES groups, as well as the cellular and molecular processes whereby pathogenesis is mediated. Such increased understanding could lead to improved approaches to prevention and treatment of cardiovascular disease.